Transgenic mice bearing a noninfectious, (i.e., replication-deficient) HIV-1 proviral genome, which lacks only the viral gag and pol genes, were generated as models for HIV pathogenesis. Heterozygous transgenics develop progressive glomerulosclerosis, as well as hyperkeratotic skin lesions. These pathologies are not unlike the HIV-associated nephropathy and hyperkeratotic skin disorders, respectively, identified in patients with AIDS. Homozygous litter-mates, in addition to displaying cutaneous disorders, suffer a syndrome of cachexia and wasting that is evident in the neonate. A similar syndrome has been described in humans that have been infected with HIV-1 in utero. The pathological and molecular biological manesfestations of these disorders were examined in transgenics by a variety of methods, including RNA analysis, immunohistochemistry, and in vitro studies that identify the cellular and viral proteins that activate the HIV transgene. HIV mRNAs are differentially expressed in various tissues, with the highest levels of expression occurring in skin, skeletal muscle, and intestine. Lesser amounts are present in kidney, as well as thymus and lymph node. At least one cellular factor, NF-KB, has been identified as a component of the viral LTR promoter transcription complex, and may play a role in tissue-specific activation. Kidneys harvested from transgenic animals show a spectrum of pathologic changes that include microcystic tubular dilation and atrophy, and an interstitial infiltrate composed mainly of macrophages and some T lymphocytes. In skin, viral gene expression is limited to differentiated keratinocytes of the epidemal stratum granulosum. The viral proteins, gp41 and gp120, have been identified in these cells. Viral gene expression in skin is enhanced by a variety of physical and chemical insults, and is correlated with an increase in the incidence of skin lesions. Additional transgenic mouse lines are being generated to help determine the particular HIV-1 gene products responsible for these cytopathic effects that occur in the absence of replicating virus.